Foot-and-mouth disease (FMD) is a major animal epidemic disease that jeopardizes the healthy development of China's animal husbandry. It mainly affects artiodactyls such as cattle, sheep and pig, and has a significant impact on the international trade of livestock and its products. Foot-and-mouth disease virus (FMDV) is a small RNA virus that has quasispecies properties of an RNA virus. Also, FMDVs contain seven serotypes and have formed many genetic lineages with geographical features due to differences in epidemic regions, each of the serotype including multiple topotypes. There are currently 3 topotypes of serotype O FMDVs in China, which are respectively South-East Asia (SEA) (O/Mya98 lineage), Middle East-South Asia (ME-SA) (O/PanAsia lineage) and Cathay (an ancient and poetic name for China and east Tartary) (O/Cathay lineage). There are larger differences among antigenic structures of the three topotypes of viruses, and thus the cross immunoprotection effect is weak. The classic O/Cathay virus strain has relatively good immunogenicity and antigenic spectrum, but a newly isolated variant of it has a weakened immunogenicity and has a tendency of immune escape. Even for a virus strain with good immunogenicity, it also cannot provide good immunoprotection against a new epidemic virus strain that has a distant genetic relationship from this virus strain when the content of vaccine antigens is low; and it is necessary to develop a multi-component antigen vaccine to improve the antigenic spectrum of the vaccine. It is more difficult to screen for a vaccine virus strain with a broad antigenic spectrum, and it is necessary to construct an excellent vaccine virus strain by reversed genetics. Neutralizing antibodies are important components of FMD protective immunity, but there are still many gaps in the study of antigenic sites revealed by FMDV broadly neutralizing antibodies.